期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 11, 期 10, 页码 1881-1885出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.9b00555
关键词
Cyclooxygenase-2; 2-arachidonylglycerol; arachidonic acid; substrate-selective inhibition
资金
- National Institutes of Health [CA89450]
- NIGMS [P30 GM124165, S10 RR029205, DEAC02-06CH11357]
We report the design, synthesis, and evaluation of a series of harmaline analogs as selective inhibitors of 2-arachidonylglycerol (2-AG) oxygenation over arachidonic acid (AA) oxygenation by purified cyclooxygenase-2 (COX-2). A fused tricyclic harmaline analog containing a CH3O substituent at C-6 and a CH3 group at the C-1 position of 4,9-dihydro-3H-pyrido[3,4-b]indole (compound 3) was the best substrate-selective COX-2 inhibitor of those evaluated, exhibiting a 2AG-selective COX-2 inhibitory IC50 of 0.022 mu M as compared to >1 mu M for AA. The 2.66 degrees resolution crystal complex of COX-2 with compound 3 revealed that this series of tricyclic indoles binds in the cyclooxygenase channel by flipping the side chain of L531 toward the dimer interface. This novel tricyclic indole series provides the foundation for the development of promising substrate-selective molecules capable of increasing endocannabinoid (EC) levels in the brain to offer new treatments for a variety of diseases, from pain and inflammation to stress and anxiety disorders.
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